Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use

ABSTRACT

The disclosure is directed to new crystalline tebipenem pivoxil salt forms, including a crystalline tebipenem pivoxil ethane sulfonate salt form (Form A), a crystalline tebipenem pivoxil ketoglutarate salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), a tebipenem pivoxil malate salt form (Form A), a tebipenem pivoxil methane sulfonate salt form (Form B), a tebipenem pivoxil hydrobromide salt form (Form B), and a tebipenem pivoxil edisylate salt form (Form A). The disclosure also includes a composition, comprising a crystalline tebipenem pivoxil salt and a pharmaceutically acceptable carrier and further includes a method for treating an antibiotic resistant bacterial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a crystalline tebipenem pivoxil salt.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application No.62/455,109, filed Feb. 6, 2017, which is hereby incorporated byreference in its entirety.

FIELD OF THE DISCLOSURE

Disclosed are solid tebipenem pivoxil salt forms, including crystallineforms, pharmaceutical compositions and preparations containing the solidtebipenem pivoxil salt forms, methods for using the crystalline forms totreat bacterial infections, and methods of manufacture of thecrystalline forms.

BACKGROUND

The molecules in a crystalline solid are arranged in a crystal lattice,a three dimensional structure in which structural units (unit cells) arerepeated in a regular manner Different crystal forms of the samesubstance (polymorphs) have distinct crystal lattices, which can resultin important differences in their properties, utilities, and commercialvalues. For example, graphite and diamond are polymorphs of crystallinecarbon. Polymorphs of pharmaceutical compounds can also be distinctly,if not as dramatically, different in their properties, includingproperties relevant to the development of formulations of suchpharmaceutical compounds and to the development of solid dosage forms,such as tablets and capsules, comprising such formulations. The crystalform of a drug may also be relevant to compliance with regulatoryrequirements concerning its manufacture.

Tebipenem pivoxil is a carbapenem antibiotic useful for treatingantibiotic resistant bacterial infections. To improve therapeutic use oftebipenem pivoxil, new solid forms, such as crystalline salt forms, aredesirable.

SUMMARY

Disclosed herein are crystalline tebipenem pivoxil salt forms. Thesecrystalline forms include a crystalline tebipenem pivoxil ethanesulfonate salt form (Form A), a crystalline tebipenem pivoxilketoglutarate salt form (Form A), tebipenem pivoxil maleate salt forms(Form A and Form B), a tebipenem pivoxil malate salt form (Form A), atebipenem pivoxil methane sulfonate salt form (Form B), a tebipenempivoxil hydrobromide salt form (Form B), and a tebipenem pivoxiledisylate salt form (Form A).

Also disclosed herein is a composition, comprising a crystallinetebipenem pivoxil salt and a pharmaceutically acceptable carrier.

Also disclosed herein is a method for treating an antibiotic resistantbacterial infection, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a crystallinetebipenem pivoxil salt.

Methods of manufacturing crystalline tebipenem pivoxil salt forms arealso included.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, advantages and features of this disclosurewill become more apparent by describing in further detail exemplaryembodiments thereof with reference to the accompanying drawings.

FIG. 1. XRPD diffractogram of crystalline tebipenem pivoxil ethanesulfonate Form A.

FIG. 2. DSC and TGA profiles of crystalline tebipenem pivoxil ethanesulfonate Form A.

FIG. 3. XRPD diffractogram of crystalline tebipenem pivoxilketoglutarate salt form A.

FIG. 4. DSC and TGA profiles of crystalline tebipenem pivoxilketoglutarate salt Form A.

FIG. 5. XRPD diffractogram of crystalline tebipenem pivoxil maleate saltform A.

FIG. 6. DSC and TGA profiles of crystalline tebipenem pivoxil maleatesalt Form A.

FIG. 7. XRPD diffractogram of crystalline tebipenem pivoxil maleate saltform B.

FIG. 8. DSC and TGA profiles of crystalline tebipenem pivoxil maleatesalt Form B.

FIG. 9. XRPD diffractogram of crystalline tebipenem pivoxil malate saltForm A prepared by method 1 in which tebipenem pivoxil is dissolved inMeCN.

FIG. 10. XRPD diffractogram of crystalline tebipenem pivoxil malate saltForm A prepared by method 2 in which tebipenem pivoxil is dissolved inMeCN.

FIG. 11. DSC and TGA profiles of crystalline tebipenem pivoxil malatesalt Form A prepared by method 1.

FIG. 12. XRPD diffractogram of crystalline tebipenem pivoxil methanesulfonate salt Form B.

FIG. 13. DSC and TGA profiles of crystalline tebipenem pivoxil methanesulfonate salt Form B.

FIG. 14. XRPD diffractogram of crystalline tebipenem pivoxilhydrobromide salt Form B.

FIG. 15. DSC and TGA profiles of crystalline tebipenem pivoxilhydrobromide salt Form B.

FIG. 16. XRPD diffractogram of crystalline tebipenem pivoxil edisylatesalt Form A.

FIG. 17. DSC and TGA profiles of crystalline tebipenem pivoxil edisylatesalt Form A.

FIG. 18. XRPD diffractogram of crystalline tebipenem pivoxil free base.

FIG. 19. XRPD diffractogram of crystalline tebipenem pivoxilhydrochloride salt Form A.

FIG. 20. DSC and TGA profiles of tebipenem pivoxil hydrochloride saltForm A.

FIG. 21. XRPD diffractogram of crystalline tebipenem pivoxilhydrobromide salt Form C.

FIG. 22. DSC and TGA profiles of crystalline tebipenem pivoxilhydrobromide salt Form C.

FIG. 23. XRPD diffractogram of crystalline tebipenem pivoxilhydrobromide salt Form D.

FIG. 24. DSC and TGA profiles of crystalline tebipenem pivoxilhydrobromide salt Form D.

FIG. 25. XRPD diffractogram of crystalline tebipenem pivoxil methanesulfonate salt Form B+C.

FIG. 26. DSC and TGA profiles of crystalline tebipenem pivoxilhydrobromide salt Form B+C.

FIG. 27. XRPD diffractogram of crystalline tebipenem pivoxil methanesulfonate salt Form D.

FIG. 28. DSC and TGA profiles of crystalline tebipenem pivoxil methanesulfonate salt Form D+Form B.

DETAILED DESCRIPTION

The disclosure now will be described in more detail, with reference tothe accompanying figures. This disclosure may, however, be embodied inmany different forms, and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the disclosure to those skilled in the art. Likereference numerals refer to like elements throughout.

Terminology

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, creams, ointments, suppositories,inhalable forms, transdermal forms, and the like.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, e.g., a crystalline tebipenem pivoxil salt, and at leastone other substance, such as a carrier, excipient, or diluent.Pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturingpractice) standards for human or non-human drugs.

The term “carrier” applied to pharmaceutical compositions describedherein refers to a diluent, excipient, or vehicle with which an activecompound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the present application includes both one and more than one suchexcipient.

A “patient” is a human or non-human animal in need of medical treatment.Medical treatment can include treatment of an existing condition, suchas a disease or disorder, prophylactic or preventative treatment, ordiagnostic treatment. In some embodiments the patient is a humanpatient.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Providing a crystalline tebipenem pivoxil salt form” with at least oneadditional active agent” means a crystalline tebipenem pivoxil salt formand the additional active agent(s) are provided simultaneously in asingle dosage form, provided concomitantly in separate dosage forms, orprovided in separate dosage forms for administration separated by someamount of time that is within the time in which both the tebipenempivoxil and the at least one additional active agent are within theblood stream of a patient. The crystalline tebipenem pivoxil salt formand the additional active agent need not be prescribed for a patient bythe same medical care worker. The additional active agent or agents neednot require a prescription. Administration of crystalline tebipenempivoxil salt form or the at least one additional active agent can occurvia any appropriate route, for example, oral tablets, oral capsules,oral liquids, inhalation, injection, suppositories or topical contact.

“Treatment,” as used herein includes providing the crystalline tebipenempivoxil salt form and at least one additional active agent sufficientto: (a) reduce probability a disease or a symptom of a disease fromoccurring in a patient who is be predisposed to the disease but has notyet been diagnosed as having it (e.g. prevent bacterial infection in apatient traveling to an area where risk of exposure to bacterialinfection is high); (b) inhibiting the disease, i.e. arresting itsdevelopment; and (c) relieving the disease, i.e., causing regression ofthe disease. “Treating” and “treatment” also means providing atherapeutically effective amount of the crystalline tebipenem pivoxilsalt form and at least one additional active agent to a patient havingor susceptible to microbial infection, such as an antibiotic resistantbacterial infection or a Gram negative bacterial infection.

A “therapeutically effective amount” of a pharmaceutical combination ofthis disclosure means an amount effective, when administered to apatient, to provide a therapeutic benefit such as an amelioration ofsymptoms, e.g., an amount effective to decrease the symptoms of abacterial infection. For example a patient infected with a bacterialinfection may present abnormal levels of certain blood cells, especiallyleukocytes (white blood cells) for example, an increase in neutrophilsand a decrease in lymphocytes. A therapeutically effect amount is thusan amount sufficient to provide a return of leukocyte levels to thenormal range. A therapeutically effective amount is also an amountsufficient to prevent a significant increase or significantly reduce thedetectable level of bacteria or bacterial antibodies in the patient'sblood, serum, or tissues.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

It will be understood that when an element is referred to as being “on”another element, it can be directly on the other element or interveningelements may be present there between. In contrast, when an element isreferred to as being “directly on” another element, there are nointervening elements present.

It will be understood that, although the terms “first,” “second,”“third” etc. may be used herein to describe various elements,components, regions, layers and/or sections, these elements, components,regions, layers and/or sections should not be limited by these terms.These terms are only used to distinguish one element, component, region,layer or section from another element, component, region, layer orsection. Thus, “a first element,” “component,” “region,” “layer” or“section” discussed below could be termed a second element, component,region, layer or section without departing from the teachings herein.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. As used herein, thesingular forms “a,” “an,” and “the” are intended to include the pluralforms, including “at least one,” unless the content clearly indicatesotherwise. “Or” means “and/or.” As used herein, the term “and/or”includes any and all combinations of one or more of the associatedlisted items. It will be further understood that the terms “comprises”and/or “comprising,” or “includes” and/or “including” when used in thisspecification, specify the presence of stated features, regions,integers, steps, operations, elements, and/or components, but do notpreclude the presence or addition of one or more other features,regions, integers, steps, operations, elements, components, and/orgroups thereof.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this disclosure belongs. It willbe further understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art and thepresent disclosure, and will not be interpreted in an idealized oroverly formal sense unless expressly so defined herein.

The tebipenem pivoxil (CAS Reg. No. 161715-24-8) has the followingstructure (1):

Disclosed herein are crystalline forms of a crystalline tebipenempivoxil ethane sulfonate salt form (Form A), a crystalline tebipenempivoxil ketoglutarate salt form (Form A), tebipenem pivoxil maleate saltforms (Form A and Form B), a tebipenem pivoxil malate salt form (FormA), a tebipenem pivoxil methane sulfonate salt form (Form B), and atebipenem pivoxil hydrobromide salt form (Form B).

Crystalline forms of a tebipenem pivoxil salt include single-componentand multiple-component crystalline forms, including, but not limited to,polymorphs, solvates, hydrates, co-crystals and clathrates. Someembodiments herein provide single-component crystalline forms of atebipenem pivoxil salt. Other embodiments herein providemultiple-component crystalline forms comprising a tebipenem pivoxilsalt. Multiple-component crystalline forms provided herein includecrystalline forms which may be described by the terms salt, co-crystal,hydrate, solvate, clathrate and/or polymorph, and include crystallineforms which may be described by one or more of these terms.

Crystalline forms comprising a tebipenem pivoxil salt can be prepared bythe methods described herein, including the methods described in theExamples below, or by techniques known in the art, including heating,cooling, freeze drying, lyophilization, quench cooling the melt, rapidsolvent evaporation, slow solvent evaporation, solventrecrystallization, antisolvent addition, slurry recrystallization,crystallization from the melt, desolvation, recrystallization inconfined spaces such as, e.g., in nanopores or capillaries,recrystallization on surfaces or templates such as, e.g., on polymers,recrystallization in the presence of additives, such as, e.g.,co-crystal counter-molecules, desolvation, dehydration, rapid cooling,slow cooling, exposure to solvent and/or water, drying, including, e.g.,vacuum drying, vapor diffusion, sublimation, grinding (including, e.g.,cryo-grinding, solvent-drop grinding or liquid assisted grinding),microwave-induced precipitation, sonication-induced precipitation,laser-induced precipitation and precipitation from a supercriticalfluid. The particle size of the resulting crystalline forms, which canvary, (e.g., from nanometer dimensions to millimeter dimensions), can becontrolled, e.g., by varying crystallization conditions, such as, e.g.,the rate of crystallization and/or the crystallization solvent system,or by particle-size reduction techniques, e.g., grinding, milling,micronizing or sonication.

While not wishing to be bound by any particular theory, certaincrystalline forms are characterized by physical properties, e.g.,stability, solubility and dissolution rate, appropriate forpharmaceutical and therapeutic dosage forms. Moreover, while not wishingto be bound by any particular theory, certain crystalline forms arecharacterized by physical properties (e.g., density, compressibility,hardness, morphology, cleavage, stickiness, solubility, water uptake,electrical properties, thermal behavior, solid-state reactivity,physical stability, and chemical stability) affecting particularprocesses (e.g., yield, filtration, washing, drying, milling, mixing,tableting, flowability, dissolution, formulation, and lyophilization)which make certain crystalline forms suitable for the manufacture of asolid dosage form. Such properties can be determined using particularanalytical chemical techniques, including solid-state analyticaltechniques (e.g., X-ray diffraction, microscopy, spectroscopy andthermal analysis), as described herein and known in the art.

Some embodiments herein provide compositions comprising one or more ofthe crystalline forms. Other embodiments provide compositions of one ormore crystalline forms in combination with other active ingredients.Certain embodiments provide methods of using these compositions in thetreatment, prevention or management of diseases and disorders including,but not limited to, the diseases and disorders provided herein.

In addition to crystalline forms comprising a tebipenem pivoxil salt,provided herein are crystalline forms comprising prodrugs of a tebipenempivoxil salt.

In addition to crystalline forms comprising a tebipenem pivoxil salt,provided herein are crystalline forms comprising prodrugs of a tebipenempivoxil salt.

Crystalline forms provided herein may also include unnatural proportionsof atomic isotopes at one or more of the atoms in a tebipenem pivoxilsalt. For example, the compound may be radiolabeled with radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) sulfur-35(³⁵S), or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic agents, e.g., anti-bacterial therapeutic agents, researchreagents, e.g., binding assay reagents, and diagnostic agents, e.g., invivo imaging agents. All isotopic variations of a tebipenem pivoxilsalt, whether radioactive or not, are intended to be encompassed withinthe scope of the embodiments provided herein.

The disclosure includes a crystalline tebipenem pivoxil ethane sulfonatesalt form, wherein the XPRD of the form, obtained from a Cu Kα source,has the characteristic 2θ values of FIG. 1 (Form A).

The disclosure includes a crystalline tebipenem pivoxil ethane sulfonatesalt form (Form A), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12, or more of the characteristic2θ values: 5.7, 8.8, 9.6, 10.8, 12.4, 13.7, 15.1, 16.9, 17.8, 18.4,18.7, 19.0, 19.3, 20.0, 20.3, 21.0, 21.8, 22.1, 22.4, 23.0, 23.4, 24.9,25.2, 25.9, 26.2, 26.5, 26.8, 27.2, 27.9, 28.6, 29.2, and 29.7+/−0.2degrees 2θ.

The disclosure includes a crystalline tebipenem pivoxil ethane sulfonatesalt form characterized by an XPRD diffractogram obtained from a Cu Kαsource which comprises peaks at 2θ values of 9.6, 12.4, 15.1, 19.0, and20.3+/−0.2 degrees 20; or 10.8, 13.7, 15.9, 22.1, and 27.9+/−0.2 degrees2θ.

The disclosure includes the crystalline tebipenem pivoxil ethanesulfonate salt form of Form A, additionally characterized by a DSCprofile substantially as shown in FIG. 2.

The crystalline tebipenem pivoxil ethane sulfonate salt form of Form Aadditionally characterized by a DSC profile having an endotherm with anonset of 70.8° C. and a minima of 90.7° C.

The disclosure includes a crystalline tebipenem pivoxil ketoglutaratesalt form (Form A), wherein the XPRD of the form, obtained from a Cu Kαsource, has the characteristic 2θ values of FIG. 3.

The disclosure includes a crystalline tebipenem pivoxil ketoglutaratesalt form (Form A), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the followingvalues: 5.4, 8.6, 9.8, 10.4, 10.7, 12.7, 13.2, 13.5, 14.0, 16.2, 17.0,17.2, 17.7, 18.0, 18.7, 18.9, 19.4, 19.6, 20.0, 20.7, 21.1, 21.6, 21.8,22.7, 23.0, 23.6, 24.6, 26.7, 27.1, 27.4, 28.3, or 28.7. 29.6

The disclosure includes crystalline tebipenem pivoxil ketoglutarate saltform (Form A0, characterized by an XPRD diffractogram obtained from a CuKα source which comprises peaks at 2θ values of 8.6, 10.7, 13.2, 16.2,and 17.2+/−0.2 degrees 2θ; or 9.8, 12.7, 13.5, 17, and 17.7+/−0.2degrees 2θ.

The crystalline tebipenem pivoxil ketoglutarate salt form of Form A,additionally characterized by a DSC profile having a DSC profilesubstantially as shown in FIG. 4.

The crystalline tebipenem pivoxil ketoglutarate salt form of Form A,additionally characterized by a DSC profile having an endotherm with anonset of 36.6° C. and a minima of 57.0° C. and a second endotherm withan onset of 106.5° C. and a minima of 117° C.

The disclosure crystalline tebipenem pivoxil maleate salt form, whereinthe XPRD of the form, obtained from a Cu Kα source, has thecharacteristic 2θ values of FIG. 5 (Form A).

The disclosure includes a crystalline tebipenem pivoxil maleate saltform (Form A), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the followingvalues: 8.0, 8.6, 10.8, 11.2, 11.9, 12.2, 12.6, 15.0, 15.4, 15.7, 16.9,18.2, 18.7, 19.4, 19.9, 20.4, 21.2, 22.5, 23.1, 24.2, 24.8, 25.7, 26.5,27.5, or 28.3.

The disclosure includes a crystalline tebipenem pivoxil maleate saltform (Form A0 characterized by an XPRD diffractogram obtained from a CuKα source which comprises peaks at 2θ values of 8, 12.6, 15.4, 16.0, and18.7+/−0.2 degrees 2θ; or 8.6, 15.0, 15.7, 19.4, and 19.9+/−0.2 degrees2θ.

The disclosure includes crystalline tebipenem pivoxil maleate salt FormA, additionally characterized by a DSC profile substantially as shown inFIG. 6.

The disclosure includes crystalline tebipenem pivoxil maleate salt FormA additionally characterized by a DSC profile having an endotherm withan onset of 50.6° C. and a minima of 74.3° C. and a second endothermwith an onset of 103.0° C. and a minima of 110.1° C.

The disclosure includes crystalline tebipenem pivoxil maleate salt form,wherein the XPRD of the form, obtained from a Cu Kα source, has thecharacteristic 2θ values of FIG. 7 (Form B).

The disclosure includes a crystalline tebipenem pivoxil maleate saltform (Form B), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the followingvalues: 5.5, 8.9, 10.1, 10.6, 11.0, 12.8, 13.6, 14.3, 14.9, 16.7, 17.0,17.2, 17.9, 18.6, 19.0, 19.4, 20.2, 20.5, 20.8, 21.4, 21.9, 22.2, 23.1,24.0, 24.5, 25.1, 25.5, 26.2, 27.5, 28.1, 28.9, or 29.6.

The disclosure includes a crystalline tebipenem pivoxil maleate saltform (Form B) characterized by an XPRD diffractogram obtained from a CuKα source which comprises peaks at 2θ values of 8.9, 13.6, 17.0, 18.6,and 20.8+/−0.2 degrees 2θ; or 11.0, 14.3, 19.0, 20.2, and 21.4+/−0.2degrees 2θ.

The disclosure includes crystalline tebipenem pivoxil maleate salt form(Form B), additionally characterized by a DSC profile substantially asshown in FIG. 8.

The disclosure includes crystalline tebipenem pivoxil maleate salt FormB additionally characterized by a DSC profile having an endotherm withan onset of 40.3° C. and a minima of 65.3° C. and a second endothermwith an onset of 114.7° C. and a minima of 119.6° C.

The disclosure includes crystalline tebipenem pivoxil malate salt form,wherein the XPRD of the form, obtained from a Cu Kα source, has thecharacteristic 2θ values of FIG. 9 (Form A).

The disclosure includes a crystalline tebipenem pivoxil malate salt form(Form A), wherein the XPRD of the form, obtained from a Cu Kα source,has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values: 9.1,9.3, 11.0, 11.8, 12.3, 12.9, 13.1, 14.4, 14.9, 15.3, 16.0, 16.6, 17.6,18.5, 19.0, 19.9, 20.5, 20.8, 21.4, 21.9, 22.2, 23.1, 23.4, 23.9, 24.8,25.5, 26.0, 26.3, 27.7, or 28.4.

The disclosure includes a crystalline tebipenem pivoxil malate salt form(Form A) characterized by an XPRD diffractogram obtained from a Cu Kαsource which comprises peaks at 2θ values of 11.8, 15.3, 17.6, 19.0, and23.9+/−0.2 degrees 2θ; or 12.9, 18.5, 20.5, 21.9, and 26.3+/−0.2 degrees2θ.

The disclosure includes a crystalline tebipenem pivoxil malate salt FormA, additionally characterized by a DSC profile substantially as shown inFIG. 11.

The disclosure includes crystalline tebipenem pivoxil malate salt Form Aadditionally characterized by a DSC profile having an endotherm with anonset of 32.8° C. and a minima at 51.1° C. and a second endotherm withan onset of 116° C. and a minima at 127.7° C.

The disclosure includes crystalline tebipenem pivoxil methane sulfonatesalt form, wherein the XPRD of the form, obtained from a Cu Kα source,has the characteristic 2θ values of FIG. 12 (Form B).

The disclosure includes a crystalline tebipenem pivoxil methanesulfonate salt form (Form B), wherein the XPRD of the form, obtainedfrom a Cu Kα source, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of thefollowing values: 9.1, 9.6, 10.9, 12.6, 13.9, 14.6, 15.4, 17.2, 17.5,18.2, 18.4, 18.7, 19.4, 19.6, 19.8, 20.4, 20.6, 21.5, 21.9, 22.2, 22.9,23.6, 24.5, 25.3, 25.6, 26.4, 26.9, 27.1, 27.5, 27.8, 28.0, 28.6, 29.4,or 29.8.

The disclosure includes a crystalline tebipenem pivoxil methanesulfonate salt form (Form B) characterized by an XPRD diffractogramobtained from a Cu Kα source which comprises peaks at 2θ values of 9.6,12.6, 15.4, 19.4, and 22.2+/−0.2 degrees 2θ; or 10.9, 13.9, 17.2, 20.4,and 23.6+/−0.2 degrees 2θ.

The disclosure includes a crystalline tebipenem pivoxil methanesulfonate salt of Form B, additionally characterized by a DSC profilesubstantially as shown in FIG. 13.

The disclosure includes crystalline tebipenem pivoxil methane sulfonatesalt Form B, additionally characterized by a DSC profile having anendotherm with an onset of 57.8° C. and a minima at 88.5° C. and asecond endotherm with an onset of 175° C. and a minima at 177° C.

The disclosure crystalline tebipenem pivoxil hydrobromide salt form,wherein the XPRD of the form, obtained from a Cu Kα source, has thecharacteristic 2θ values of FIG. 14 (Form B).

The disclosure includes a crystalline tebipenem pivoxil hydrobromidesalt form (Form B), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the followingvalues: 9.3, 9.5, 10.7, 12.6, 13.0, 14.0, 15.2, 15.7, 17.6, 18.7, 19.1,20.0, 20.4, 20.8,21.1, 21.9, 22.6, 23.5, 23.7, 24.9, 25.3, 25.5, 25.8,26.1, 26.5, 26.8, 27.3, 27.6, 28.4, 28.8, 29.4, 29.7, or 29.9+/−0.2degrees 2θ.

The disclosure crystalline tebipenem pivoxil hydrobromide salt form(Form B) characterized by an XPRD diffractogram obtained from a Cu Kαsource which comprises peaks at 2θ values of 9.6, 13.0, 17.6, 20.8, and26.8+/−0.2 degrees 2θ; or 10.7, 14.0, 18.7, 20.0, and 23.5+/−0.2 degrees2θ.

The crystalline includes tebipenem pivoxil hydrobromide salt Form Badditionally characterized by a DSC profile substantially as shown inFIG. 15.

The disclosure includes crystalline tebipenem pivoxil methane sulfonatesalt Form A additionally characterized by a DSC profile having anendotherm with an onset of 32.9° C. and a minima at 66.3° C. and asecond endotherm with an onset of 186.8° C. and a minima at 190.8° C.

The disclosure includes a crystalline tebipenem pivoxil edisylate saltform, wherein the form, obtained from a Cu Kα source, has thecharacteristic 2θ values of FIG. 16.

The disclosure includes a crystalline tebipenem pivoxil edisylate saltform (Form A), wherein the XPRD of the form, obtained from a Cu Kαsource, has any 5, 6, 7, 8, 9, 10, 11, 12 or more of the followingvalues: 4.1, 5.0, 7.7, 8.2, 8.5, 9.5, 10.1, 13.1, 13.5, 15.4, 16, 16.9,17.3, 18, 19.1, 20.3, 20.7, 21.2, 22.7, 23.1, 24.5, 25.7, 27.3,28.8+/−0.2 degrees 2θ.

A crystalline tebipenem pivoxil edisylate salt form (Form A)characterized by an XPRD diffractogram obtained from a Cu Kα sourcewhich comprises peaks at 2θ values of 4.1, 8.2, 10.1, 20.3, and21.2+/−0.2 degrees 2θ; or 5.0, 10.1, 15.4, 18.0, and 20.7+/−0.2 degrees2θ.

The disclosure includes crystalline tebipenem pivoxil edisylate saltForm A characterized by a DSC profile substantially as shown in FIG. 17.

The disclosure includes a crystalline tebipenem pivoxil edisylate saltform (Form A) characterized by a DSC profile having an endotherm with anonset of 56.3° C. and a minima at 79.3° C. and a second endotherm withan onset of 144.5° C. and a minima at 157.5° C.

The disclosure includes a crystalline tebipenem pivoxil salt form of anyone of FIG. 1, 3, 5, 7, 9, 10, 12, 14, 16, 21, or 23 wherein thecrystalline tebipenem pivoxil salt form is at least 90%, 95%, 97%, 98%,99% ot 99.5% pure.

The disclosure includes a pharmaceutical composition comprising atebipenem pivoxil salt and a physiologically acceptable carrier, whereinthe tebipenem pivoxil salt comprises at least 90%, 95%, 97%, 98%, 99% ot99.5% of a crystalline tebipenem pivoxil salt of FIG. 1, 3, 5, 7, 9, 10,12, 14, 16, 21, or 23. The pharmaceutical composition can be anintraarterial, intravenous, injectable, topical, mucosal, parenteral(including subcutaneous, intramuscular, or bolus injection), sublingual,transdermal, buccal, or oral dosage form. The composition can be an oraldosage form, for example, in the form of a tablet or capsule.

In some embodiments, pharmaceutical compositions and dosage formsprovided herein include one or more crystalline forms including atebipenem pivoxil salt.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of bacterial infection or a related disorder maycontain larger amounts of one or more of the active ingredients itcomprises than a dosage form used in the chronic treatment of the samedisease. Similarly, a parenteral dosage form may contain smaller amountsof one or more of the active ingredients it comprises than an oraldosage form used to treat the same disease or disorder. These and otherways in which specific dosage forms encompassed by this invention willvary from one another will be readily apparent to those skilled in theart. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms provided herein lie withinthe range of from about 1 mg to about 1,000 mg per day, given as asingle once-a-day dose in the morning but preferably as divided dosesthroughout the day. More specifically, the daily dose is administeredtwice daily in equally divided doses. Specifically, a daily dose rangemay be from about 5 mg to about 500 mg per day, more specifically,between about 10 mg and about 200 mg per day. In managing the patient,the therapy may be initiated at a lower dose, perhaps about 1 mg toabout 25 mg, and increased if necessary up to about 200 mg to about1,000 mg per day as either a single dose or divided doses, depending onthe patient's global response.

Oral dosage forms. Pharmaceutical compositions of the invention that aresuitable for oral administration can be presented as discrete dosageforms, such as, but are not limited to, tablets (e.g., chewabletablets), caplets, capsules, and liquids (e.g., flavored syrups). Suchdosage forms contain predetermined amounts of active ingredients, andmay be prepared by methods of pharmacy well known to those skilled inthe art. See generally Remington's Pharmaceutical Sciences, 18th ed.,Mack Publishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101™, AVICEL-PH-103™, AVICELRC-581™, AVICEL-PH105™ (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581™. Suitable anhydrous orlow moisture excipients or additives include AVICEL-PH-103™ and Starch1500LM™.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200™, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL™ (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about one weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Delayed Release Dosage Forms. Crystalline forms comprising a tebipenempivoxil salt as provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral Dosage Forms. Parenteral dosage forms can be administered topatients by various routes including, but not limited to, subcutaneous,intravenous (including bolus injection), intramuscular, andintraarterial. Because their administration typically bypasses patients'natural defenses against contaminants, parenteral dosage forms arepreferably sterile or capable of being sterilized prior toadministration to a patient. Examples of parenteral dosage formsinclude, but are not limited to, solutions ready for injection, dryproducts ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms. Transdermal, topical,and mucosal dosage forms of the invention include, but are not limitedto, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments,gels, solutions, emulsions, suspensions, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.Further, transdermal dosage forms include “reservoir type” or “matrixtype” patches, which can be applied to the skin and worn for a specificperiod of time to permit the penetration of a desired amount of activeingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80™(polysorbate 80) and Span 60™ (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different crystalline forms comprising theactive ingredients can be used to further adjust the properties of theresulting composition.

Kits. This invention encompasses kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a patient.

A typical kit of the invention comprises a unit dosage form of atebipenem pivoxil salt, or a pharmaceutically acceptable crystallineform or prodrug thereof, and a unit dosage form of a second activeingredient. Examples of second active ingredients include, but are notlimited to, those listed herein.

Kits of the invention can further comprise devices that are used toadminister the active ingredient(s). Examples of such devices include,but are not limited to, syringes, drip bags, patches, and inhalers.

Kits of the invention can further comprise pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a crystalline formthat must be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:Water for Injection USP; aqueous vehicles such as, but not limited to,Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure includes a method for treating a bacterial infection,comprising administering to a patient in need of such treatment atherapeutically effective amount of a pharmaceutical compositioncontaining a crystalline tebipenem pivoxil salt of FIG. 1, 3, 5, 7, 9,10, 12, 14, or 16. The method can include administering a crystallinetebipenem pivoxil salt, wherein the composition contains an active agentin addition to the crystalline tebipenem pivoxil salt. The method caninclude administering the crystalline tebipenem pivoxil salt to thepatient in combination with an active agent. The active agent can be anantibiotic. The bacterial infection can a Gram negative bacterialinfection such as an E. coli infection, a Klebsiella pneumoniaeinfection, an Acinetobacter baumannii infection, a Pseudomonasaeruginosa, a Neisseria gonorrhoeae infection, or a Yersinia pestisinfection.

Specific methods of the invention can comprise the administration of anadditional therapeutic agent such as, but not limited to,anti-inflammatory drugs, antihistamines and decongestants. Examples ofsuch additional therapeutic agents include, but are not limited to:antihistamines including, but not limited to, ethanolamines,ethylenediamines, piperazines, and phenothiazines; antiinflammatorydrugs; NSAIDS, including, but not limited to, aspirin, salicylates,acetominophen, indomethacin, sulindac, etodolac, fenamates, tolmetin,ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen,flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolon derivatives;and steroids including, but not limited to, cortical steroids andadrenocortical steroids.

As stated above, certain crystalline forms comprising a tebipenempivoxil salt may be used in the treatment or prevention of a wide rangeof bacterial infections. The magnitude of a prophylactic or therapeuticdose of a particular active ingredient of the invention in the acute orchronic management of a disease or condition may vary with the natureand severity of the disease or condition and the route by which theactive ingredient is administered. The dose, and perhaps the dosefrequency, will also vary according to the age, body weight, andresponse of the individual patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors. In general, the recommended daily dose range for theconditions described herein lie within the range of from about 1 mg toabout 1,000 mg per day, given as a single once-a-day dose preferably asdivided doses throughout a day. More specifically, the daily dose isadministered twice daily in equally divided doses. Specifically, a dailydose range may be from about 5 mg to about 500 mg per day, morespecifically, between about 10 mg and about 200 mg per day.Specifically, the daily dose may be administered in 5 mg, 10 mg, 15 mg,20 mg, 25 mg, 50 mg, or 100 mg dosage forms. In managing the patient,the therapy should be initiated at a lower dose, perhaps about 1 mg toabout 25 mg, and increased if necessary up to about 200 mg to about1,000 mg per day as either a single dose or divided doses, depending onthe patient's global response. Alternatively, the daily dose is from0.01 mg/kg to 100 mg/kg.

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual patient response.

As stated above, the pharmaceutical composition of the disclosure mayalso contain a pharmaceutically acceptable carrier, which can be anypharmaceutically acceptable excipient such as a binder, filler,lubricant, solvent, disintegrant or coating. Examples ofpharmaceutically acceptable carrier are provided above.

The crystalline tebipenem pivoxil salt is generally present within apharmaceutical composition in a therapeutically effective amount. Asused herein, a “therapeutically effective amount” (or dose) is an amountthat, upon administration to a patient, results in a discernible patientbenefit. It will be apparent that the therapeutically effective amountwill depend upon the particular patient, the indication for which it isadministered, as well as the effects of any co-administered drugs.

As also stated above, in an embodiment the composition may be suitablefor pharmaceutical use and may be in the form of a pharmaceuticalcomposition. The pharmaceutical composition may have any suitable form,and may be a tablet, capsule, solution, suspension, or a combinationthereof.

The pharmaceutical composition may be used to treat a disorder, e.g., abacterial infection. Therapeutic methods provided herein may be used totreat an existing disorder, or to prevent, decrease the severity of, ordelay the onset of a disorder in a patient. Alternatively, or inaddition, compounds provided herein may be administered to a patient toprevent infection in a healthy patient. Patients include humans,domesticated companion animals (pets, e.g., dogs) and livestock animals.A method for treating a disorder may comprise administering to a patientin need of treatment a therapeutically effective amount of thepharmaceutical composition.

Pharmaceutical compositions may be packaged or used for the manufactureof a medicament for treatment. Packaged pharmaceutical preparationsinclude a container holding a therapeutically effective amount of thecrystalline tebipenem pivoxil salt and may further include labeling(e.g., instructions) indicating that the contained composition is to beused for treating the disorder.

This disclosure is further illustrated by the following examples thatshould not be construed as limiting.

EXAMPLES Instrumental Techniques

The following instrumental techniques are used for analysis of allcrystal forms unless otherwise noted.

X-Ray Powder Diffraction (XRPD)

X-Ray Powder Diffraction patterns were collected on a Bruker D8diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-2θ goniometer,and divergence of V4 and receiving slits, a Ge monochromator and aLynxeye detector. The instrument is performance checked using acertified Corundum standard (NIST 1976). The software used for datacollection was Diffrac Plus XRD Commander v2.6.1 and the data wereanalysed and presented using Diffrac Plus EVA v15.0.0.0. Samples wererun under ambient conditions as flat plate specimens using powder asreceived. The sample was gently packed into a cavity cut into polished,zero-background (510) silicon wafer. The sample was rotated in its ownplane during analysis. The details of the data collection are: Angularrange: 2 to 42° 2θ, step size: 0.05° 2θ and collection time: 0.5 s/step.

Differential Scanning Calorimetry (DSC)

DSC was conducted with a TA Instruments Q100 differential scanningcalorimeter equipped with an autosampler and a refrigerated coolingsystem under 40 mL/min N₂ purge. DSC thermograms were obtained at 5°C./min in crimped Al pans.

DSC data were also collected on a TA Instruments Q2000 equipped with a50 position auto-sampler. The calibration for thermal capacity wascarried out using sapphire and the calibration for energy andtemperature was carried out using certified indium. Typically 0.5-3 mgof each sample, in a pin-holed aluminium pan, was heated at 10° C/minfrom 25° C. to 300° C. A purge of dry nitrogen at 50 ml/min wasmaintained over the sample.

Thermogravimetric Analysis (TGA)

TGA thermograms were obtained with a TA Instruments Q500thermogravimetric analyzer, equipped with a 16 position auto-sampler,under 40 mL/min N₂ purge at 5° C./min in Pt or Al pans. The instrumentwas temperature calibrated using certified alumel and nickel. Typically5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan andheated at 10° C./min from ambient temperature to 300° C. A nitrogenpurge at 60 ml/min was maintained over the sample.

High Pressure Liquid Chromotography (HPLC)

Purity analysis was performed on an Agilent HP1100 series systemequipped with a diode array detector and using ChemStation softwarevB.04.03 using the Method A of Method B as detailed below.

TABLE A HPLC Method A for chemical purity determinations Parameter ValueType of method Reverse phase with gradient elution Sample Preparation0.5 mg/ml in acetonitrile Column Supelco Ascentis Express C18, 100 × 4.6mm, 2.7 μm Column Temperature (° C.) 25 Injection (1) 3 or 5 Wavelength,Bandwidth (nm) 255, 90 Flow Rate (ml/min)  2 Phase A 0.1% TFA in waterPhase B 0.085% TFA in acetonitrile Time (min) % Phase A % Phase BTimetable 0 95 5 6 5 95 6.2 95 5 8 95 5

HPLC analysis was performed according to Method B on an AgilentHP1100/1200 system equipped with a diode array detector and usingChemstation software. The analysis was conducted by using a reversephase column Agilent LiChrospher 100 RP-18, 5 μm, 250×4 mm underisocratic conditions at ambient temperature. Before injection, thesample concentration was approximately 0.5 mg/mL in 1:1acetonitrile-water mixture (volume to volume), and the injection sizewas 10 μL. The mobile phase was 68/30/2 (volume/volume/volume) 50 mMammonium acetate in water/acetonitrile/ triethylamine, pH was adjustedto 3.5 with concentrated phosphoric acid. The flow rate was 0.8 mL/min,and the run time was 15 minutes. The detection took place at 330 nmwavelength.

Proton Nuclear Magnetic Resonance (¹H NMR)

NMR spectra were collected on a Bruker 400 MHz instrument equipped withan auto-sampler and controlled by a DRX400 console. Automatedexperiments were acquired using ICON-NMR v4.0.7 running with Topspinv1.3 using the standard Bruker loaded experiments. Samples were preparedat a concentration of 2-5 mg/mL by dissolution in DMSO-d6 solvent.Off-line analysis was carried out using ACD Spectrus Processor 2014.

Comparative Example 1 Crystalline Form of Tebipenem Pivoxil

Crystalline tebipenem pivoxil Form A was prepared according to knownmethods. An XRPD diffractogram of crystalline tebipenem pivoxil wasobtained (FIG. 18). The crystalline tebipenem pivoxil XRPD diffractogramexhibited the peaks listed in Table 1.

TABLE 1 Characteristic angles of Tebipenem Pivoxil (2θ) Form ACharacteristic angle (°) Relative intensity (%) 9.55 29.12 11.00 25.0612.80 23.14 13.25 21.78 15.40 20.77 17.95 100.00 19.20 20.32 20.35 51.6921.10 64.79 23.85 33.18 25.80 21.78 26.40 20.65 27.75 23.36 28.75 24.2737.50 25.62

DSC data (now shown) of crystalline tebipenem pivoxil shows a sharpendotherm at 132.1° C. followed by two distinct exotherms at 161.8 and175.9° C. TGA showed gradual degradation beginning at about 109.5° C.and rapid degradation after 169.2° C. Crystalline tebipenem pivoxilexhibited approximately 2% weight loss between 109.5° C. and 169.2° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.16 (m, 15H) 1.19 (s, 1H)1.98-1.99 (m, 1H) 2.73 (s, 1H) 2.89 (s, 1H) 3.07 (s, 1H) 3.24 (dd,J=6.25, 2.59 Hz, 1H) 3.27-3.27 (m, 1H) 3.31-3.38 (m, 3H) 3.73 (td,J=6.79, 3.60 Hz, 2H) 3.87 (t, J=7.58 Hz, 2H) 3.91-4.01 (m, 1H) 4.03 (d,J=7.07 Hz, 1H) 4.18 (dd, J=9.35, 2.65 Hz, 1H) 4.27-4.39 (m, 3H) 5.09 (d,J=5.18 Hz, 1H) 5.74 (d, J=5.94 Hz, 1H) 5.89 (d, J=5.94 Hz, 1H) 7.95 (s,1H).

Comparative Example 2 Crystalline Tebipenem Pivoxil Hydrochloride (HCL)Salt Form A

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL). The acid stocksolution (1 M HCl in THF) was then added to 1 mol eq. and stirred at 25°C., 500 rpm using a magnetic stir bar in a Polar Bear device for 20minutes. The sample was then cooled to 0° C. over a 2 hour period (0.2°C./min) and maintained at 0° C. for about 2 hours. The suspensionobtained was filtered using a fritted filter and air-dried on a filterblock at ambient for 15 minutes. This sample was found to be 99.5% pureby HPLC (Method A). The XRPD diffractogram for this crystalline form isprovided in FIG. 19 and the peak listing appears in Table 2.

Crystalline tebipenem pivoxil HCl salt of the same form was alsoobtained at equivalent purity using the method in the precedingparagraph with the following changes. Tebipenem pivoxil was dissolved inEtOH (930 μL). The acid stock solution (1 M HCl in THF) was then addedto 1 mol eq. and stirred at 25° C., 500 rpm using a magnetic stir bar ina Polar Bear device for 20 minutes. The sample was then cooled to 5° C.over 2 hours (0.2 ° C./min) and maintained at 5° C. for about 2 hours.

TABLE 2 Characteristic angles (2θ) of Tebipenem Pivoxil HydrochlorideSalt Form A Characteristic angle (°) Relative intensity (%) 6.2 4.6 7.22.8 9.4 17.5 10.9 14.1 12.5 3.5 12.6 7.1 13 7.8 14.1 3.7 15.4 9.9 15.82.3 17.9 100 18.1 4.1 19.1 4.8 20.2 29.4 20.9 29.1 21.1 9.2 21.9 1.922.1 3.4 22.8 6.1 23.7 12.8 23.8 10.5 25.2 5.6 25.5 7.1 25.7 4.7 26.13.9 26.3 8.5 26.8 3.3 27.1 7.5 27.7 8.4 28.3 3.6 28.6 8.1 29.1 2.7 29.43.3 30 5

The DSC profile for crystalline tebipenem pivoxil (FIG. 20)hydrochloride salt Form A shows a broad endotherm having an onset of29.4° C. with a minima at 56° C. and an enthalpy of fusion of 38 J/g.The DSC also shows an exotherm at the onset of degradation at 194.8° C.

TGA (also shown in FIG.17) showed at 2.2% weight loss from roomtemperature to 100° C. No other thermal events were recorded until theonset of degradation at about 150° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.18 (m, 15H) 2.08 (s, 1H) 3.28(dd, J=6.19, 2.65 Hz, 1H) 3.30-3.41 (m, 2H) 3.42-3.42 (m, 1H) 3.61-3.68(m, 2H) 3.89-4.01 (m, 3H) 4.14-4.27 (m, 3H) 4.40-4.50 (m, 1H) 4.69-4.81(m, 2H) 5.14 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H)10.46 (s, 1H). ¹H NMR and HPLC were repeated 1 week post storage at 40°C./75% relative humidity. Tebipenem pivoxil hydrochloride saltcrystalline form A was obtained and determined to be 98.9% pure by HPLC.

Example 1 Crystalline Tebipenem Pivoxil Ethane Sulfonate (ESA) Salt

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL), then the acidstock solution (1 M ethane sulfonic acid in THF) was added to 1 mol eq.and stirred at 25° C., 500 rpm using a magnetic stir bar in a Polar Beardevice (Cambridge Reactor Design for 20 minutes. The sample was thencooled to 0° C. over a 2 hour period (0.2° C./min) and then maintainedat 0° C. for ˜2 hours. No precipitation was observed. The sample wasthen cooled by 0.5° C./min to −15° C. at 0.5° C./min and stored at −20°C. for 2 days. The solution was transferred to a 20 mL scintillationvial and antisolvent (tert-methyl butyl ether, TBME) was added slowlywhilst stirring at 25° C., 500 rpm until a precipitate formed at a ratioof 10:1 antisolvent:solvent (v/v). The suspension obtained was filteredusing a fritted filter and air-dried on a filter block at ambient for 15minutes.

The XRPD spectra for crystalline tebipenem pivoxil ethane sulfonate FormA is shown in FIG. 1. The XRPD diffractogram for this crystalline formexhibited the characteristic peaks listed in Table 3. The sample oftebipenem pivoxil ethane sulfonate (esylate) salt crystalline Form A wasdetermined to be 98.9% pure by HPLC, Method A.

XRPD and HPLC analysis were performed again after one week of storage at40° C., 75% relative humidity. The XPRD spectra was substantiallyunchanged, however the sample was found to have a substantially lowerpurity of be 80.7% by HPLC Method A.

TABLE 3 Characteristic angles (2θ) of Tebipenem Pivoxil Ethane SulfonateSalt Form A Characteristic angle (°) Relative intensity (%) 5.7 23.7 8.812.8 9.6 29.5 10.8 45.5 12.4 29.8 13.7 32.5 15.1 84.4 16.9 87.1 17.8 2318.4 29.8 18.7 41.6 19.0 100 19.3 46.1 20.0 22 20.3 55.5 21.0 40 21.823.6 22.1 89.5 22.4 14.9 23.0 29.4 23.4 16.4 24.9 11.8 25.2 16.4 25.9 3026.2 17.1 26.5 19.1 26.8 19.1 27.2 17 27.9 48.7 28.6 15.8 29.2 16.3 29.716.5

The DSC profile for crystalline tebipenem pivoxil (FIG. 2) ethanesulfonate salt Form A shows a broad endotherm having an onset of 70.8°C. with two minima, the first at 90.7° C. and the second atapproximately 108° C. with an enthalpy of fusion of 116 J/g for thefirst minima and 19 J/g for the second. Degradation occurs above 150° C.for this form.

TGA (also shown in FIG. 2) showed gradual degradation from roomtemperature to 110° C. with a 2.9% weight loss. No other thermal eventswere recorded until the onset of degradation beginning at about 150° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (t, J=7.45 Hz, 3H) 1.07-1.16 (m,15H) 2.35 (q, J=7.37 Hz, 2H) 3.07 (s, 1H) 3.28 (dd, J=6.13, 2.72 Hz, 1H)3.34 (s, 17H) 3.60-3.68 (m, 2H) 3.93 (br t, J=7.52 Hz, 3H) 4.12-4.17 (m,1H) 4.19 (br d, J=9.47 Hz, 2H) 4.21-4.24 (m, 1H) 4.40-4.49 (m, 1H)4.68-4.77 (m, 2H) 5.11 (br d, J=4.80 Hz, 1H) 5.75 (d, J=5.81 Hz, 1H)5.88 (d, J=5.94 Hz, 1H) 10.11 (br s, 1H). ¹H NMR was consistent withpure tebipenem pivoxil. 1.0 eq. of the esylate counterion was observed.

Example 2 Crystalline Tebipenem Pivoxil Ketoglutarate Salt (IPTG) Form A

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL). The acid stocksolution (1 M malic acid in THF) was then added to 1 mol eq. and stirredat 25° C., 500 rpm using a magnetic stir bar in a Polar Bear device for20 minutes. The sample was then cooled to 5° C. over 2 hours (0.25°C./min) and maintained at 5° C. for ˜2 hours. No precipitation wasobserved so the sample was cooled to −15° C. at 0.5° C./min and storedat −20° C. for 2 days. The solution was transferred to a 20 mLscintillation vial and antisolvent (tert-methyl butyl ether, TBME) wasadded slowly whilst stirring at 20° C., 500 rpm at a ratio of 10:1antisolvent:solvent (v/v). A precipitate formed after stirring for 24hours, which was filtered using a fritted filter and air-dried on afilter block at ambient for 15 minutes.

The XRPD spectra for crystalline tebipenem pivoxil ketoglutarate saltForm A is shown in FIG. 3. The XRPD diffractogram for this crystallineform exhibited the characteristic peaks listed in Table 4. The sample oftebipenem pivoxil ketoglutarate salt crystalline Form A was determinedto be 94.5% pure by HPLC, Method A.

An attempt was made to repeat the XRPD and HPLC analysis after one weekof storage at 40° C., 75% relative humidity. Post storage XPRD spectracould not be obtained as the sample deliquesced.

TABLE 4 Characteristic angles (2θ) of Tebipenem Pivoxil KetoglutarateSalt Form A Characteristic angle (°) Relative intensity (%) 5.4 21.1 8.642.6 9.8 18.6 10.4 11 10.7 13.7 12.7 36.5 13.2 27 13.5 51.7 14.0 30.116.2 42.8 17.0 80.6 17.2 100.0 17.7 82.9 18.0 16.5 18.7 59.1 18.9 28.319.4 25.1 19.6 58.3 20.0 77.8 20.7 37 21.1 64.2 21.6 39.7 21.8 29 22.728.5 23.0 37 23.6 56.9 24.6 18.6 26.7 35.4 27.1 26.3 27.4 22.6. 28.317.8 28.7 25.2 29.6 18

The DSC profile for crystalline tebipenem pivoxil (FIG. 4) ketoglutaratesalt Form A shows a broad endotherm having an onset of 36.6° C. with anda minima at 57.0° C. with an enthalpy of fusion of 10 J/g, a secondendotherm having an onset of 106.5° C. and a minima 117.0° C., with aheat of melting of 12 J/g, and an exotherm with a peak at 126.4° C.during degradation.

TGA (also shown in FIG. 4) shows 0.7% weight loss from room temperatureto 75° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.17 (m, 16H) 2.45 (t, J=6.63 Hz,2H) 2.85 (br t, J=6.25 Hz, 2H) 2.97-2.97 (m, 1H) 3.24-3.27 (m, 2H)3.28-3.40 (m, 21H) 3.43 (s, 4H) 3.81-3.92 (m, 4H) 3.93-4.00 (m, 1H) 4.18(dd, J=9.47, 2.65 Hz, 1H) 4.31-4.38 (m, 1H) 4.44 (d, J=8.46 Hz, 2H)4.98-4.98 (m, 1H) 5.10 (br s, 1H) 5.74 (d, J=5.81 Hz, 1H) 5.89 (d,J=5.94 Hz, 1H). ¹H NMR was consistent with pure tebipenem pivoxil. 1.0eq. of the ketoglutarate counterion was observed.

Example 3 Crystalline Tebipenem Pivoxil Maleate (MAE) Salt Form A

Tebipenem pivoxil (J07492, 35 mg) was dissolved in MeCN (270 μL), thenthe acid stock solution (1 M maleic acid in THF) was added to 1 mol eq.and stirred at 25° C., 500 rpm using a magnetic stir bar in a Polar Beardevice for 20 minutes. The sample was then cooled to 0° C. over a 2 hourperiod (0.2° C./min) and maintained at 0° C. for approximately 1-2hours. The solution was transferred to a 20 mL scintillation vial andantisolvent (tert-methyl butyl ester, TBME) was added slowly whilestirring at 20° C., 500 rpm to a ratio of 4:1 antisolvent:solvent (v/v).A precipitate formed after stirring for 24 hours, which was filteredusing a fritted filter and air-dried on a filter block at ambient for 15minutes.

The XRPD spectra for crystalline tebipenem pivoxil maleate salt Form Ais shown in FIG. 5. The XRPD diffractogram for this crystalline formexhibited the characteristic peaks listed in Table 5. The sample oftebipenem pivoxil maleate salt crystalline Form A was determined to be99.3% pure by HPLC, Method A.

XRPD and HPLC analyses were repeated after one week of storage at 40°C., 75% relative humidity. The XRPD diffractogram showed that Form A hadconverted to Form B. The tebipenem pivoxil maleate salt Form B, poststorage, was 78.6% pure by HPLC, Method A.

TABLE 5 Characteristic Angles (2θ) of Tebipenem Pivoxil Maleate SaltForm A Characteristic angle (°) Relative intensity (%) 8.0 36.9 8.6 22.710.8 13.0 11.2 16.7 11.9 16.4 12.2 20.1 12.6 58.2 15.0 43.6 15.4 44.615.7 42.0 16.9 36.5 18.2 37.4 18.7 100 19.4 43.9 19.9 66.0 20.4 44.021.2 33.9 22.5 24.4 23.1 20.6 24.2 24.4 24.8 51.0 25.7 37.8 26.5 41.427.5 17.8 28.3 21.0

The DSC profile for crystalline tebipenem pivoxil (FIG. 6) maleate saltForm A shows a broad melting endotherm having an onset of 50.6° C. witha minima at 74.3° C. with an enthalpy of fusion of 53 J/g, a secondendotherm having an onset of 103.0° C. and a minima 110.1° C., with anenthalpy of fusion of 32 J/g, and an exotherm with a peak at 139.5° C.prior to degradation.

TGA (also shown in FIG. 6) shows 3.6% weight loss from room temperatureto 100° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.18 (m, 16H) 2.07 (s, 1H) 3.07 (s,1H) 3.07-3.08 (m, 1H) 3.12-3.12 (m, 1H) 3.27 (dd, J=6.19, 2.78 Hz, 2H)3.34 (br dd, J=9.28, 7.26 Hz, 5H) 3.60 (t, J=7.52 Hz, 2H) 3.89-4.01 (m,3H) 4.07-4.22 (m, 3H) 4.38-4.47 (m, 1H) 4.67 (td, J=8.87, 3.85 Hz, 2H)5.11 (br d, J=5.05 Hz, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz,1H) 6.05 (s, 2H). ¹H NMR was consistent with pure tebipenem pivoxil.0.97 eq. of the maleate counterion was observed.

Example 4 Crystalline Tebipenem Pivoxil Maleate (MAE) Salt Form B

Crystalline tebipenem pivoxil maleate salt Form B was prepared asfollows. Tebipenem pivoxil (mg) was dissolved in MeCN (270 μL). The acidstock solution (1 M maleic acid in THF) was then added to 1 mol eq. andstirred at 25° C., 500 rpm using a magnetic stir bar in a Polar Beardevice for 20 minutes. The sample was then cooled to 5° C. over a 2 hourperiod (0.25° C./min) and maintained at 5° C. for approximately 2 hours.No precipitation was observed. The sample was then cooled to −15° C. at0.5° C./min and stored at −20° C. for 2 days. The solution wastransferred to a 20 mL scintillation vial and antisolvent (tert-methylbutyl ether, TBME) was added slowly whilst stirring at 25° C., 500 rpm,at a ratio of 5:1 antisolvent:solvent (v/v). A precipitate formed afterstirring for 24 hours. The precipitate was filtered using a frittedfilter and air-dried on a filter block at ambient for 15 minutes.

The XRPD diffractogram for this crystalline form exhibited thecharacteristic peaks listed in Table 6.

The XRPD spectra for crystalline tebipenem pivoxil maleate salt Form Bis shown in FIG. 7. The sample of tebipenem pivoxil maleate saltcrystalline Form B was determined to be 99.3% pure by HPLC, Method A.

The XRPD and HPLC analysis were repeated after one week of storage at40° C., 75% relative humidity. The XRPD diffractogram showedcharacteristic peaks for tebipenem pivoxil maleate crystalline Form B.The tebipenem pivoxil maleate salt Form B, post storage, was 90.2% pureby HPLC, Method A.

TABLE 6 Characteristic angles (2θ) of Tebipenem Pivoxil Maleate AcidSalt Form B Characteristic angle (°) Relative intensity (%) 5.5 24 8.929.1 10.1 14.7 10.6 10.1 11.0 34.5 12.8 15.7 13.6 25.5 14.3 19.8 14.96.8 16.7 28.4 17.0 88.2 17.2 29.6 17.9 7.4 18.6 41.8 19.0 29.1 19.4 14.520.2 32.7 20.5 16.2 20.8 53.9 21.4 100 21.9 25.8 22.2 26.3 23.1 14.524.0 43 24.5 11.3 25.1 11.8 25.5 16.3 26.2 16.2 27.5 17.8 28.1 19.1 28.916.8 29.6 10.6

The DSC profile for crystalline tebipenem pivoxil (FIG. 8) maleate saltForm B shows a broad endotherm having an onset of 40.3° C. with a minimaat 65.3° C. and an enthalpy of fusion of 77 J/g, a second endothermhaving an onset of 114.7° C. and a minima of 119.6° C., with an enthalpyof fusion of 25 J/g, and an exotherm with a peak at 140.3° C. prior todegradation.

TGA (also shown in FIG. 8) shows 4.6% weight loss from room temperatureto 100° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm −0.21-−0.21 (m, 1H) 1.07-1.16 (m, 15H)3.07 (s, 1H) 3.27 (dd, J=6.19, 2.78 Hz, 2H) 3.29-3.40 (m, 23H) 3.60 (t,J=7.52 Hz, 2H) 3.89-4.02 (m, 3H) 4.06-4.16 (m, 2H) 4.19 (dd, J=9.54,2.72 Hz, 1H) 4.37-4.48 (m, 1H) 4.61-4.73 (m, 2H) 5.11 (d, J=5.18 Hz, 1H)5.75 (d, J=5.81 Hz, 1H) 5.89 (d, J=5.94 Hz, 1H) 6.05 (s, 2H). ¹H NMR wasconsistent with pure tebipenem pivoxil. Approximately 0.92 eq. of themaleate counterion was observed.

Example 5 Crystalline Tebipenem Pivoxil Malate (MAL) Salt Form A

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL). The acid stocksolution (1 M malic acid in THF) was added to 1 mol eq. and stirred at25° C., 500 rpm using a magnetic stir bar in a Polar Bear device for 20minutes. The sample was then cooled to 0° C. over a 2 hour period (0.2°C./min) and maintained at 0° C. for about 2 hours. No precipitation wasobserved so the sample was cooled to −15° C. at 0.5° C./min and storedat −20° C. for 2 days. The solution was transferred to a 20 mLscintillation vial and antisolvent (tert-methyl butyl ether, TBME) wasadded slowly while stirring at 25° C., 500 rpm at a ratio of 4:1antisolvent:solvent (v/v). A precipitate formed after stirring for 24hours, which was filtered using a fritted filter and air-dried on afilter block at ambient for 15 minutes. The XPRD diffractogram forcrystals prepared according to this procedure is shown in FIG. 9. Thepeak listing for this diffractogram is provided in Table 7.

Crystalline tebipenem pivoxil malate salt was also obtained atequivalent purity using the method in the preceding paragraph but withthe following changes. Tebipenem pivoxil was dissolved in EtOH (930 μL).The acid stock solution (1 M malic acid in THF) was added to 1 mol eq.and stirred at 25° C., 500 rpm using a magnetic stir bar in a Polar Beardevice for 20 minutes. The sample was then cooled to 5° C. overapproximately 2 hours (0.2° C./min) and maintained at 5° C. for about 2hours. The sample was subsequently cooled to −15° C. at 0.2° C./min andstored at −20° C. for 24 hours. The solution was transferred to a 20 mLscintillation vial and antisolvent (n-hexane) was added slowly whilststirring at 25° C., 500 rpm until a precipitate formed at a ratio of 3:1antisolvent:solvent (v/v). The suspension obtained was filtered using afritted filter and air-dried on a filter block at ambient for 15minutes. The XPRD for crystals prepared by this method is shown in FIG.10.

TABLE 7 Characteristic angles (2θ) Tebipenem Pivoxil Malate Salt Form ACharacteristic angle (°) Relative intensity (%) 9.1 22.9 9.3 18.7 11.011.4 11.8 25.4 12.3 12.9 12.9 23.6 13.1 21.4 14.4 11.9 14.9 14.2 15.335.1 16.0 20.1 16.6 15.9 17.6 89.3 18.5 56.5 19.0 100 19.9 26.6 20.581.6 20.8 28.6 21.4 20.6 21.9 37.1 22.2 33.1 23.1 14.9 23.4 16.2 23.936.8 24.8 20.4 25.5 17.2 26.0 20.1 26.3 27.1 27.7 25.9 28.4 24.4

The DSC profile for crystalline tebipenem pivoxil (FIG. 11) malate saltForm A shows a melting endotherm having an onset of 32.1° C. with aminima at 51.1° C. and an enthalpy of fusion of 9 J/g, with a secondendotherm having an onset of 117.0° C. and a minima 127.6° C., with aheat of melting of 23 J/g, and an exotherm with a peak at 131.6° C. witha heat of 44 J/g.

TGA (also shown in FIG.11) shows 0.7% weight loss from room temperatureto 75° C., and a 0.3% weight loss from 75° C. to 130° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.16 (m, 16H) 2.41 (dd, J=15.66,7.20 Hz, 1H) 2.59 (dd, J=15.60, 5.75 Hz, 1H) 3.07 (s, 1H) 3.25 (dd,J=6.32, 2.65 Hz, 1H) 3.32 (br dd, J=9.35, 7.33 Hz, 5H) 3.39 (t, J=7.52Hz, 3H) 3.68-3.68 (m, 1H) 3.76-3.83 (m, 2H) 3.88 (t, J=7.58 Hz, 2H) 3.96(br s, 1H) 4.15-4.18 (m, 1H) 4.15-4.22 (m, 1H) 4.29-4.44 (m, 3H)5.04-5.04 (m, 1H) 5.09 (br s, 1H) 5.74 (d, J=5.94 Hz, 1H) 5.89 (d,J=5.94 Hz, 1H). ¹H NMR was consistent with pure tebipenem pivoxil.Approximately 1.09 eq. of the malate counterion was observed. XPRD wasattempted one week post storage at 40° C. and 75% relative humidity. Thesample was found to have deliquesced to an orange liquid. No HPLCanalysis of the post storage sample was performed.

Example 6 Tebeipenem Pivoxil Methane Sulfonate Salt (MSA) Form B

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL). The acid stocksolution (1 M methane sulfonic acid in THF) was then added to 1 mol eq.and stirred at 25° C., 500 rpm using a magnetic stir bar in a Polar Beardevice for 20 minutes. The sample was then cooled to 0° C. over 2 hours(0.2° C./min) and maintained at 0° C. for about 2 hours. Noprecipitation was observed so the sample was cooled to −15° C. at 0.5°C./min and stored at −20° C. for 2 days. The solution was transferred toa 20 mL scintillation vial and antisolvent (tert-methyl butyl ether,TBME) was added slowly whilst stirring at 25° C., 500 rpm until aprecipitate formed at a ratio of 3:1 antisolvent:solvent (v/v). Thesuspension obtained was filtered using a fritted filter and air-dried ona filter block at ambient for 15 minutes. Crystalline material obtainedby this procedure was determined to be 99.5% pure by HPLC, Method A. TheXRPD diffractogram for this form is shown in FIG. 12. Characteristicpeaks are listed in Table 8.

The MSA salt was also obtained in the same crystalline form atequivalent purity using the method in the preceding paragraph but withthe following changes. Tebipenem pivoxil was dissolved in EtOH (930 μL).The acid stock solution (1 M methane sulfonic acid in THF) was added to1 mol eq. and stirred at 25° C., 500 rpm using a magnetic stir bar in aPolar Bear device for 20 minutes. The sample was then cooled to 5° C.over approximately 2 hours (0.2° C./min) and maintained at 5° C. forabout 2 hours. The sample was subsequently cooled to −15° C. at 0.2°C./min and stored at −20° C. for 24 hours. The solution was transferredto a 20 mL scintillation vial and antisolvent (n-hexane) was addedslowly whilst stirring at 25° C., 500 rpm until a precipitate formed ata ratio of 3:1 antisolvent:solvent (v/v). The suspension obtained wasfiltered using a fritted filter and air-dried on a filter block atambient for 15 minutes.

TABLE 8 Characteristic angles (2θ) of Tebipenem Pivoxil MethaneSulfonate Salt Form B Characteristic angle (°) Relative intensity (%)9.1 10.8 9.6 31.5 10.9 33.8 12.6 24.6 13.9 27 14.6 6.2 15.4 54.5 17.290.1 17.5 12.4 18.2 17.2 18.4 41.7 18.7 30.7 19.4 100 19.6 66.5 19.833.1 20.4 67.1 20.6 20.5 21.5 46.9 21.9 17.1 22.2 99.8 22.9 18 23.6 23.424.5 12.2 25.3 11.1 25.6 13.8 26.4 16.3 26.9 22.3 27.1 15.8 27.5 9 27.813.1 28.0 24.1 28.6 32.1 29.4 25.8 29.8 13.8

The DSC profile for crystalline tebipenem pivoxil (FIG. 13) methanesulfonate salt Form B shows a melting endotherm having an onset of 57.8°C. with a minima at 88.5° C. and a heat of melting of 105 J/g, a secondendotherm having an onset of 175.2° C. and a minima 177.0° C., with aheat of melting of 48 J/g prior to degradation.

TGA (also shown in FIG.13) shows 2.9% weight loss from room temperatureto 100° C. No other thermal events were note until the onset ofdegradation.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.18 (m, 16H) 2.07 (s, 1H) 2.30 (s,2H) 2.27-2.31 (m, 1H) 3.07 (s, 1H) 3.28 (dd, J=6.13, 2.59 Hz, 1H)3.30-3.46 (m, 6H) 3.61-3.69 (m, 2H) 3.90-4.01 (m, 3H) 4.13-4.28 (m, 3H)4.40-4.50 (m, 1H) 4.70-4.79 (m, 2H) 5.11 (br s, 1H) 5.75 (d, J=5.94 Hz,1H) 5.88 (d, J=5.94 Hz, 1H) 10.12 (br s, 1H). ¹H NMR (not shown) wasconsistent with pure tebipenem pivoxil. Approximately 1.06 eq. of themethane sulfonate counterion was observed when the analysis was adjustedfor solvent by TGA. XPRD and HPLC were performed one week post storageat 40° C. and 75% relative humidity. The XPRD diffractogram wasconsistent with pure tebipenem pivoxil methane sulfonate crystallineForm B. The sample was 99.0% pure by HPLC, Method A.

Example 7 Large Scale Preparation of Tebipenem Pivoxil HBR MethaneSulfonate Salt (MSA) Form B

Tebipenem Pivoxil (125 mg) was placed into eight separate 20 mlscintillation vials and dissolved in MeCN (7.5 vol, 940 μl) whilestirring at 25° C., 500 rpm using a magnetic stirrer bar on a Polar Beardevice. The sample was treated with 1 mol eq. of the acid stock (1Mmethane sulphonic acid stock in THF) and cooled to 5° C. Noprecipitation was observed at 5° C., and the temperature was raised to20° C. Antisolvent (TBME) was then added, whilst stirring at 20° C. to a2:1 ratio (antisolvent:solvent (v/v) ratio) for 1 hour. The resultingsuspensions were filtered through a fritted filter, dried under suctionfor 15 minutes and each sample analysed by XRPD. Samples exhibiting theXRPD pattern of mesylate Form B were pooled together forcharacterisation. Characteristic peaks of the XRPD diffractogram arelisted in Table 10.

TABLE 9 Solid-state characterisation of scaled-up Tebipenem Pivoxil MSAForm B Obtained by Antisolvent addition at 20° C. (TBME:MeCN, 2:1) XRPDCrystalline, Mesylate Form B ¹H NMR ¹H NMR consistent with supplied.~1.03 eq Mesylate, ~0.03 eq ACN Anion IC (eq.) 0.97 (not adjusted forsolvent) HPLC, Method B 99.4% GVS (Gravimetric Vapor Sample ishygroscopic. 6.2% Sorption) and XRPD analysis uptake from 0 to 90% RH.post GVS Isotherm shows steps from 0 to 10% RH (3.0% wt.) and 80 to 90%RH (1.4% wt.). No change by XRPD post GVS. DSC Broad endo at 68.8° C.(onset), 88 J/g. Endo at 140.7° C. (onset), 16 J/g, prior to degradation~160° C. TGA 3.5% wt. loss from RT to 120° C. KF 3.3% water, ~1 eq.water PLM Crystals and particles, 10-150 μm diameter XRPD analysis poststorage at Unchanged by XPRD after 1 40° C./75% RH and 25° C./ week, andwas a powder post- 97% RH for 1-4 weeks 25/97 but a gum post-40/75. HPLCafter 1 week: 40/75: 95.5%, 25/97: 96.5%. Sample deliquesced within 2weeks VT-XRPD on C2 Some changes upon heating up to 100° C. Sampledegrades ~160° C.

TABLE 10 Peak listing for XRPD diffractogram of MSA salt Form B Angle(2-Theta °) Intensity (%) 9.1 6.7 9.7 17.9 10.9 19.6 12.6 16.7 13.9 15.915.4 35 17.2 52.1 17.5 8.8 18.2 14 18.4 19.9 18.7 18.1 19.4 100 19.640.2 19.8 20.9 20.4 36.2 21.5 25.3 21.9 8.4 22.2 45.1 22.9 10.1 23.611.6 24.5 6.2 25.3 6.3 25.5 8.2 26.5 8.3 26.8 12.4 27.5 5.5 28 10.5 28.616.4 29.3 11.3

Example 8 Tebeipenem Pivoxil Methane Sulfonate Salt (MSA) Form C

Tebipenem Pivoxil (1 g) was dissolved in MeCN (8 vol, 8 ml) and 1 moleq. of the acid stock (1 M methane sulphonic acid in THF, 2 ml) addedwhilst stirring at 25° C., 500 rpm. Antisolvent (TBME) was then added toa 2:1 ratio (antisolvent:solvent (v/v) ratio) and a precipitate began toform. Further antisolvent was added to a ratio of 5:1 and theprecipitate was then cooled to 0° C. at 0.2° C./min On reaching 0° C.the sample was removed and rapidly cooled in a dry ice/acetone bath tocomplete precipitation. The solid was filtered under vacuum into aBuchner funnel and dried under vacuum at RT for 16 hours.

XRPD analysis of the resulting solid showed the material was a mixtureof mesylate Form C and Form B. A sample of pure Form C could not begenerated, therefore this sample was further characterised as detailedbelow. The XRPD diffractogram for Form C+Form B is provided at FIG. 25and the DSC and TGA plots are provided at FIG. 26.

TABLE 11 Solid-state characterisation of Tebipenem Pivoxil Mesylate FormC + Form B Obtained by Antisolvent addition at 25° C. (TBME:MeCN, 2:1)XRPD Crystalline, Mesylate Form C + Form B ¹H NMR ¹H NMR consistent withsupplied. ~1.08 eq Mesylate. Trace residual MeCN and TBME seen. Anion IC(eq.) 1.01 (not adjusted for solvent) HPLC, Method B 99.1% GVS and XRPDSample is hygroscopic. 10.0% uptake from 0 to 90% analysis post RH, withtwo steps at 0-10% & 80-90% RH GVS Reversible uptake and loss. XRPDpost-GVS showed conversion to mesylate Form B. DSC Broad endotherm from30 to 120° C. Peak at 88.2° C., 75 J/g. Sample degrades ~140° C. TGA3.5% wt. loss from RT to 120° C. KF N/P PLM N/P XRPD analysis Sampledeliquesced to an orange liquid within post storage at 1 week. No XRPDanalyses collected 40° C./75% RH and 25° C./97% RH for 1-4 weeks VT-XRPDon C2 No changes upon heating. Sample melt/ degrades ~140° C.

Example 9 Tebeipenem Pivoxil Methane Sulfonate Salt (MSA) Form D

Tebipenem Pivoxil (30 mg) was dissolved in t-BuOH (30 vol., 940 μl)while stirring at 50° C., 500 rpm using a magnetic stirrer bar on aPolar Bear device. The sample was treated with 1 mol eq. of acid stock(1 M HBr aq. in THF, 60 μl), then frozen in a dry ice/acetone bath andlyophilised for 16 hours. To the resulting white solid was added THF (30vol, 900 μl) while stirring at 25° C., 500 rpm. The suspension washeated to 50° C. and then cooled to 5° C. at 0.2° C./min and held at 5°C. for 12 hours. An aliquot of the suspension was filtered on aMillipore 96-well filter block, dried under suction for 10 minutes andanalysed by XRPD (denoted as sample ID_EMP_01). The suspension wasstirred at 25° C. for 4 hours and then filtered on a Millipore 96-wellfilter block, dried under vacuum for 10 minutes and analysed by XRPD.

XRPD analysis of an aliquot of solid post-cooling showed the materialwas mesylate Form D. After maturing at 25° C. for 4 hours, XRPD analysisshowed a mixture of mesylate Form D and Form B. A sample of pure Form Dcould not be generated by scale-up experiments, therefore this samplewas further characterised as detailed in Table 12. The XRPD for thiscrystalline form is shown in FIG. 27.

TABLE 12 Solid-state characterisation of Tebipenem Pivoxil MSA Form Didentified from screens XRPD post- Storage at 40° C./ cooling, XRPD 75%RH pre- post- and 25° C./ maturation maturation DSC TGA ¹H NMR HPLC 97%RH MSA MSA Broad endo 3.8% wt. Consistent 99.6% Sample Form D Form from30 to loss with converted to D + 100° C. from structure, Form B afterForm B (onset), RT to 0.98 eq. 1 week at 40° C./ 95.4 J/g, 100° C. MSA,75% RH. sharp endo 0.03 eq. Purity: 99.4% at 173.2° C. THF after 1 week(onset) 41 J/g. at 40° C./75% RH.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.18 (m, 16H) 1.76 (br t, J=2.78Hz, 1H) 2.29 (d, J=1.01 Hz, 3H) 2.48-2.52 (m, 1H) 3.28 (dd, J=6.13, 2.34Hz, 1H) 3.63 (t, J=7.45 Hz, 2H) 3.89-4.02 (m, 3H) 4.10-4.26 (m, 3H) 4.44(br s, 1H) 4.66-4.78 (m, 2H) 5.11 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H)5.88 (d, J=5.94 Hz, 1H) 10.10 (br s, 1H). ¹H NMR was consistent withpure tebipenem pivoxil.

Characteristic peaks of the XRPD diffractogram are listed in Table 13and the XRPD spectra is shown in FIG. 27. The DSC and TGA profiles forForm B+D are shown in FIG. 28.

TABLE 13 Peak listing for XRPD diffractogram of MSA Form D Angle(2-Theta °) Intensity (%) 4.3 44.4 7.2 21 8 15.6 8.7 19 11.2 9.8 12.617.6 12.9 11.8 13.8 11.6 14.5 10.7 16.1 100 16.7 73.1 17.2 31.1 17.520.8 17.8 92.3 18.5 64 19.1 54.3 20 48 20.2 54 20.4 29.8 20.7 51.1 21.330.3 21.6 17.2 21.8 17.4 22.3 18.2 23.2 27.8 23.7 19.5 24.6 21.1 25.226.9 26.8 22 27.5 13.5

Example 10 Crystalline Tebipenem Pivoxil Hydrobromide (HBR) Salt Form B

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μL). The counterion(1 M HBr stock in THF) was added to 1 mol eq. and stirred at 25° C., 500rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. Thesample was then cooled to 0° C. over 2 hours (0.2° C./min) andmaintained at 0° C. for ˜2 hours. The suspension obtained was filteredusing a fritted filter and air-dried on a filter block at ambient for 15minutes. This material was 99.4% pure by HPLC, Method A. The XRPDdiffractogram for tebipenem pivoxil HBr crystalline Form B prepared bythis method is shown in FIG. 14 and the peak listing is provided inTable 14.

HBr salt was also obtained at equivalent purity using the method in thepreceding paragraph but with the following changes. Tebipenem pivoxilwas dissolved in EtOH (930 μL). The counterion (1 M HBr stock in THF)was added to 1 mol eq. and stirred at 25° C., 500 rpm using a magneticstirrer bar in a Polar Bear device for 20 minutes. The sample was thencooled to 5° C. over 2 hours (0.2° C./min) and maintained at 5° C. forabout 2 hours.

TABLE 14 Characteristic angles (2θ) of Tebipenem Pivoxil HBr Salt Form BCharacteristic angle (°) Relative intensity (%) 9.3 50.6 9.5 10 10.719.5 12.6 7.2 13.0 17.9 14.0 10.1 15.2 6 15.7 6.2 17.6 100 18.7 17.519.1 9.9 20.0 79.4 20.4 13.8 20.8 70.3 21.1 14.4 21.9 10.3 22.6 11.823.5 27.2 23.7 11.4 24.9 11.6 25.3 11.5 25.5 17.4 25.8 11.7 26.1 18.426.5 10.7 26.8 19.9 27.3 17.1 27.6 16 28.4 19 28.8 13.1 29.4 12.1 29.715.2 29.9 8.6

The DSC profile for crystalline tebipenem pivoxil (FIG. 15) hydrogenbromide salt Form B shows a broad melting endotherm having an onset of32.9° C. with a minima at 66.3° C. and a heat of melting of 34.1 J/g,and an exotherm having an onset of 186.8° C., with a maxima of 190.8prior to degradation.

TGA (also shown in FIG.15) shows 1.9% weight loss from room temperatureto 100° C. No other thermal events were noted until the onset ofdegradation.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.18 (m, 15H) 3.28 (dd, J=6.19,2.65 Hz, 1H) 3.30-3.40 (m, 5H) 3.61-3.69 (m, 2H) 3.90-4.01 (m, 3H)4.13-4.27 (m, 3H) 4.41-4.50 (m, 1H) 4.69-4.79 (m, 2H) 5.00-5.01 (m, 1H)5.11 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.11(s, 1H). ¹H NMR was consistent with pure tebipenem pivoxil.Approximately 1.04 eq. of the hydrogen bromide counterion was observedwhen the analysis was adjusted for solvent by TGA. XPRD and HPLC wereperformed one week post storage at 40° C. and 75% relative humidity. TheXPRD diffractogram was consistent with pure tebipenem pivoxil HBrcrystalline Form B. The sample was 99.2% pure by HPLC.

Example 11 Crystalline Tebipenem Pivoxil Hydrobromide (HBR) Salt Form C

Tebipenem Pivoxil (30 mg) was dissolved in t-BuOH (940 μl) whilsestirring at 50° C., 500 rpm using a magnetic stirrer bar in a Polar Beardevice. The sample was treated with 1 mol eq. of acid stock (1 M HBr aq.in THF, 60 μl), then frozen in a dry ice/acetone bath and lyophilisedfor 16 hours. To the resulting white solid was added 1,2-dimethoxyethane(10 vol, 300 μl) whilst stirring at 50° C. Additional solvent was addedto a final volume of 30 vol. (900 μl) to allow effective stirring of thesuspension. The suspension was cooled to 5° C. at 0.2° C./min, andmaintained at 25° C. for 72 hours. The suspension obtained was filteredon a Millipore 96-well filter block and dried under suction for 15minutes.

TABLE 15 Solid-state characterisation of Tebipenem Pivoxil HBr Form CXRPD Crystalline, Form C ¹H NMR Consistent with HBr salt Form A Noresidual solvent. HPLC 99.8% (%, AUC) DSC No significant thermal eventsuntil exotherm at onset of degradation, at 179.5° C. (onset). TGA 0.5%wt. loss from RT to 140° C. and an onset of degradation of 181.8° C.XRPD analysis Unchanged by XRPD (Form C). post storage at Peak intensitydecreased, 40° C./75% RH for suggesting reduced crystallinity. 1 weekHPLC purity post-storage = 99.9% Anion IC 0.92 eq. (not adjusted forsolvent) GVS and XRPD N/P post-GVS

Characteristic peaks of the XRPD diffractogram are listed in Table 16.

TABLE 16 Peak listing for XRPD diffractogram of Tebipenem Pivoxil HBrForm C Angle (2-Theta °) Intensity % 4.4 72.6 8.7 15.6 9.3 17.1 12 18.413.1 21.4 13.6 11.3 14.2 5.8 15.5 10.4 16.3 29.7 16.5 20.8 17.1 18.117.3 21.4 17.6 19.3 18.5 9.6 19.3 14.4 19.7 18.7 20.8 26.1 21 21.4 21.320.7 21.7 100 22.2 21.3 22.6 22.2 22.8 11.6 23.5 23.1 24 12.1 24.4 6.525.2 17.7 25.5 17.4 26.4 13.8 26.7 15.2 27.4 6.5 28.2 14 28.8 21.3 2911.8 29.5 18.6 29.7 10.4 30 16.2 30.5 10.1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.18 (m, 15H) 3.28 (dd, J=6.00,2.46 Hz, 1H) 3.30-3.39 (m, 5H) 3.64 (t, J=7.52 Hz, 2H) 3.93 (br t,J=7.52 Hz, 3H) 4.11-4.28 (m, 3H) 4.39-4.51 (m, 1H) 4.66-4.80 (m, 2H)5.11 (br d, J=3.92 Hz, 1H) 5.75 (d, J=5.81 Hz, 1H) 5.88 (d, J=5.81 Hz,1H) 10.10 (s, 1H). ¹H NMR was consistent with pure tebipenem pivoxil.

Example 12 Crystalline Tebipenem Pivoxil Hydrobromide (HBR) Salt Form D

Tebipenem Pivoxil (2.5 g) was dissolved in the minimum volume of t-BuOH(25 vol, 62.5 ml) whilE stirring at 50° C., 600 rpm using a magneticstirrer bar in a Polar Bear device. The sample was treated with 1 moleq. of acid stock (1 M HBr aq. in THF, 4 ml), then frozen in a dryice/acetone bath and lyophilised for 16 hours. The resulting white solidwas crushed in a pestle and mortar, and dried in a vacuum oven at 60°C., 4 hrs. Once dried, the material (1.2 g) was placed into a 20 mlscintillation vial and stirred using a magnetic stirrer bar in diethylether (12.5 vol, 15 ml) at 50° C., 500 rpm, 30 minutes. The samples weresubsequently cooled from 50 to 5° C. at 0.2° C./min and then stirred at25° C. for 24 hours. The suspension obtained was filtered into a Buchnerflask and dried under vacuum for 20 minutes.

TABLE 17 Solid-state characterisation of Tebipenem Pivoxil HBr Form DXRPD Form D ¹H NMR Consistent with HBr salt Form B No residual solvent.HPLC (%, AUC) 98.8% Method B DSC Broad endotherm from RT to 100° C.(37.4° C., onset, 5 J/g). Exotherm during degradation at 162.8° C.(onset). TGA 0.5% wt. loss from RT to 100° C. No other events untildegradation. XRPD analysis post Converted to HBr Form B within 1 storageat 40° C./75% week at 25° C./97% RH, and RH or 25° C./97% RH deliquescedat 40° C./75% RH for 1 wk within 1 week. Anion IC 0.97 eq. Br KF 0.2%water GVS and XRPD post- Sample shows an initial uptake of GVS 3.0% wtfrom 40 to 90% RH, then reversible uptake and loss. Total of 4.0-4.5% wtuptake 0 to 90% RH. XRPD post-GVS showed a mixture of HBr Form B andForm D VT XRPD No form changes during or post- VT-XRPD VH XRPD No formchanges during or post- VH-XRPD

Characteristic peaks of the XRPD diffractogram are listed in Table 18and the XPRD diffractogram is provided at FIG. 23.

TABLE 18 Peak listing for XRPD diffractogram of HBr Form D Angle(2-Theta °) Intensity (%) 4.4 61.7 8.3 9.1 8.6 27 8.8 21.1 10.2 5.4 10.95.8 13.3 15.1 14.2 36.9 15.6 5.5 16.3 34 16.7 14.4 17.1 25.9 17.3 13.517.8 12.7 18 15.4 18.3 19 18.8 29.8 20.7 24.6 21 30.3 21.7 100 22.3 40.323 9.7 23.4 9.3 23.9 20.2 24.6 9.4 24.9 12.5 25.2 11.3 26.1 17.7 26.514.2 26.8 7.5 27.3 9.4 27.5 9.8 28.6 21.9 28.9 16.5 29.7 10.8

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.21 (m, 15H) 3.28 (dd, J=5.94,2.27 Hz, 1H) 3.30-3.52 (m, 4H) 3.65 (t, J=7.52 Hz, 2H) 3.88-4.01 (m, 3H)4.19 (br dd, J=9.22, 2.02 Hz, 3H) 4.45 (br d, J=5.18 Hz, 1H) 4.66-4.81(m, 2H) 4.95-5.28 (m, 1H) 5.75 (d, J=5.81 Hz, 1H) 5.88 (d, J=5.94 Hz,1H) 10.11 (br s, 1H). ¹H NMR was consistent with pure tebipenem pivoxil.

Example 13 Crystalline Tebipenem Pivoxil Edisylate (EDSA) Salt Form A

Tebipenem pivoxil (30 mg) was dissolved in MeCN (320 μL). The counterion(1 M ethane disulfonic acid stock solution in THF) was added to 0.5 moleq. and stirred at 25° C., 500 rpm using a magnetic stir bar in a PolarBear device for 20 minutes. The sample was then cooled to 5° C. over 2hours (0.25° C./min) and maintained at 5° C. for ˜1 hour. A precipitatewas obtained which was filtered using a fritted filter and air-dried ona filter block at ambient for 15 minutes. The XRPD diffractogram fortebipenem pivoxil edisylate crystalline Form A prepared by this methodis shown in FIG. 16 and the peak listing is provided in Table 19. Thecrystalline material was found to be 94.6% pure by HPLC.

TABLE 19 Characteristic angles (2θ) of Tebipenem Pivoxil Edisylate SaltForm A Characteristic angle (°) Relative intensity (%) 4.1 100 5.0 80.77.7 20.9 8.2 52.8 8.5 23.4 9.5 21.2 10.1 27.7 13.1 16.8 13.5 15.1 15.422.9 16 22 16.9 27 17.3 32.1 18 37.4 19.1 32.1 20.3 47.6 20.7 46.2 21.262.9 22.7 16.6 23.1 25.1 24.5 23.3 25.7 24.6 27.3 31.4 28.8 20.3

The DSC profile for crystalline tebipenem pivoxil edisylate salt Form A(FIG. 17) shows a broad melting endotherm having an onset at 56.3° C.with a minima at 79.3° C. and an enthalpy of fusion of 69 J/g and asmall endotherm having an onset of 144.5° C. with a minima of 157.5° C.and an enthalpy of fusion of 14 J/g.

The TGA for tebipenem pivoxil edisylate salt form A (also shown in FIG.17) shows a 4.0% weight loss from room temperature to 160° C. No otherthermal events were noted prior to the onset of degradation.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.19 (m, 15H) 2.01-2.08 (m, 1H)2.07 (s, 1H) 2.61 (s, 2H) 3.27 (dd, J=6.19, 2.78 Hz, 1H) 3.34 (s, 17H)3.62 (t, J=7.52 Hz, 2H) 3.89-4.01 (m, 3H) 4.09-4.24 (m, 3H) 4.39-4.49(m, 1H) 4.70 (td, J=8.87, 4.36 Hz, 2H) 5.11 (d, J=5.18 Hz, 1H) 5.75 (d,J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.12 (br s, 1H). ¹H NMR wasconsistent with pure tebipenem pivoxil. Approximately 0.47 equivalentsof the edisylate counterion and 0.24 equivalents MeCN solvent wereobserved. Three days post storage at 40° C. and 75% relative humiditythe sample was found to be deliquesced.

Example 14 Large Scale Preparation of Tebipenem Pivoxil HBR

In a 20 L reactor flask, equipped with thermometer and dropping funneland mechanical stirring, immersed in an empty tub, tebipenem pivoxil(1.00 kg, 2.01 mol, 1.0 eq, 99.5% HPLC purity) was dissolved in 8.0 Lacetonitrile. The solution (fully transparent) was stirred at rt. In aseparate round bottom flask, the HBr in acetonitrile solution wasprepared. 1.5 L acetonitrile was stirred in a RBF, then cooled in anicebath. At 5° C. was added 230 mL HBr solution (48% aq.) (1.0 eq HBrwith respect to tebipenem pivoxil) at such a rate that temp. did notexceed 10° C. (˜15 mins) The HBr solution (T adjusted to 0° C. prior toaddition) was added at a rate of 33 mL min-1 (requiring 1 h total) tothe solution of tebipenem pivoxil, from a 1 L dropping funnel (thefunnel was replenished during addition). After approximately 0.5 L ofthe HBr solution was added, precipitation was evident. The mixture wascooled to 5° C. and stirred 1 h. The mixture was filtered over a largeP3 glass filter and the cake was washed with 1 L acetonitrile at RT. Thefilter cake was dried on the filter 30min, then transferred to dish anddried under vacuum with N2 bleed. The tebipenem pivoxil hydrobromide(0.970 g, 1.68 mol, 83.6% yield, 99.2% HPLC purity) was determined to bedry by NMR (not shown) and packaged in a large 2 L jar and stored 2-85°C.

Example 15 Stability Studies

Salt screen results using Tebipenem Pivoxil free base are summarized inTable 20.

TABLE 20 Salt screen results using free base Salt Malate Maleate EsylateExample No. Example 5 Example 4 Example 1 HPLC (AUC) 97.3% (Method A)99.3% (Method A) 99.0% (Method A) 99.3% (Method B) 99.8% (Method B)99.8% (Method B) XRPD and HPLC analysis Deliquesced, orange MAE Form BESA Form A(yellow post-storage at 40° C./75% liquid 78.6% (Method A)solid) RH 1 week 80.7% (Method A)

Characterisation of Tebipenem Pivoxil edisylate salt obtained fromscreens on free form in acetonitrile is summarized in Table 21.

TABLE 1 Characterization of Tebipenem Pivoxil edisylate salt obtainedfrom screens on free form in acetonitrile HPLC (%, AUC), Method A 94.6%XRPD analysis post storage at Deliquesced (within 3 days) 40° C./75% RH1 week

TABLE 2 Results from repeated salt screens using the free base inacetonitrile Example No. Example 4 Example 2 Example 1 XRPD Maleate FormB Ketoglutarate Esylate Form A Form A XRPD and HPLC Maleate Form BDeliquesced Deliquesced/ analysis post- 90.2% gum storage at 40° C./(Method A) 75% RH for 1 week

While the subject matter of this disclosure has been described withreference to exemplified embodiments, it will be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted for elements thereof without departing from the scope ofthe disclosure. In addition, many modifications may be made to adapt aparticular situation or material to the teachings without departing fromthe essential scope thereof. Therefore, it is intended that thedisclosure not be limited to the particular disclosed embodiments, butwill include all embodiments falling within the scope of the appendedclaims.

1-40. (canceled)
 41. A crystalline tebipenem pivoxil hydrobromide saltform, wherein the XPRD of the form, obtained from a Cu Kα source, hasthe characteristic 2θ values of FIG.
 14. 42. A crystalline tebipenempivoxil hydrobromide salt form characterized by an XPRD diffractogramobtained from a Cu Kα source which comprises peaks at 2θ values of 9.3,13.0, 17.6, 20.8, and 26.8+/−0.2 degrees 2θ; or 10.7, 14.0, 18.7, 20.0,and 23.5+/−0.2 degrees 2θ.
 43. A crystalline tebipenem pivoxilhydrobromide salt form of claim 42 characterized by an XPRDdiffractogram obtained from a Cu Kα source which comprises peaks at 2θvalues of 9.3, 10.7, 13.0, 14.0, 17.6, 18.7, 20.0, 20.8, 23.5, and 26.8.44. The crystalline tebipenem pivoxil hydrobromide salt form of claim42, additionally characterized by a DSC profile substantially as shownin FIG.
 15. 45. The crystalline tebipenem pivoxil hydrobromide salt formof claim 42 additionally characterized by a DSC profile having anendotherm with an onset of 32.9° C. and a minima at 66.3° C. and asecond endotherm with an onset of 186.8° C. and a maxima at 190.8° C.46. A pharmaceutical composition comprising a tebipenem pivoxil salt anda physiologically acceptable carrier, wherein the tebipenem pivoxil saltcomprises at least 90% of the crystalline tebipenem pivoxil hydrobromidesalt of claim
 42. 47. A dosage form comprising the pharmaceuticalcomposition of claim 46, wherein the dosage form is an intravenous,injectable, topical, or oral dosage form.
 48. The dosage form of claim47, wherein the dosage form in the form of a tablet or capsule.
 49. Amethod for treating a bacterial infection, comprising administering to apatient in need thereof a therapeutically effective amount of thecrystalline tebipenem pivoxil hydrobromide salt form of claim
 42. 50.The method according to claim 49, wherein the patient is a human. 51.The method of claim 50, wherein the bacterial infection is a urinarytract infection.
 52. The composition of claim 46, wherein thecomposition contains a second active agent in addition to thecrystalline tebipenem pivoxil hydrobromide salt form.
 53. Thecomposition of claim 52, wherein the second active agent is anantibiotic.
 54. The method of claim 49, wherein a second active agent isadministered to the patient in combination the crystalline tebipenempivoxil hydrobromide salt.
 55. The method of claim 54, wherein thesecond active agent is an antibiotic.
 56. The method of claim 46,wherein the bacterial infection is a Gram negative bacterial infection,an E. coli infection, a Klebsiella pneumoniae infection, anAcinetobacter baumannii infection, a Pseudomonas aeruginosa, a Neisseriagonorrhoeae infection, or a Yersinia pestis infection.